(T1330-03-18) Equilibrium Solubility, Thermodynamic Modeling and Solubility Parameters of Itraconazole in Solvent Mixtures at Various Temperatures

Purpose: The main purpose of this study is to described the solubility trend and the solvent synergistic effect of drug in chlorinated methane (chloroform and dichloromethane) and primary alcohol mixtures using the Hildebrand and the Hansen solubility parameters, and to utilize them in the preformulation and formulation development stages.

Methods: The equilibrium solubility was performed by using the shake-flask method at various different temperatures. The concentration of drug was determined using the HPLC system. The solid-state properties were analyzed using DSC, TGA, and PXRD analyses. The correlation models were fitted to describe the correlation between solubility data and factors affecting it (temperature and initial composition ratio of mixture) using statistics software (IBM SPSS 26.0 version).

Results: The experimental solubility showed a maximum solubility in binary mixtures at 0.9 mass fraction of chlorinated methane. The highest maximum solubility value was observed in the binary solvent mixtures using methanol as the primary alcohol. In particular, the solubility measured at 298.15 K for methanol + 0.9 mass fraction of chlorinate was about 1000 times higher than that for pure methanol. These profiles may result from the synergistic effect of solvent mixture and can be described using solubility parameters. The Hansen solubility parameter for binary mixtures decreased as the mass fraction of chlorinated methane increased. In addition, the solubility data were fitted by association with various correlation models, and it was confirmed to provide reliable predictions from the estimated RAD and RMSD values.

Conclusion: The experimentally obtained data evaluated in this study showed that itraconazole solubility in the chlorinated methane + primary alcohol mixtures increased with increasing temperature and the ratio of chlorinated methane. It was found to exhibit the highest solubility value in a solvent mixture of methanol with 0.9 mass fraction of chloroform (w₁). In addition, these results are related to solvent synergy and can be explained by the three-dimensional solubility parameter space (Ra) that is solubility parameters. The experimental solubility data and the predicted data will be useful in the development stage such as preformulation and formulation studies to improve the solubility and dissolution of poorly soluble drugs.

Mole fraction solubility of itraconazole in dichloromethane + primary alcohol mixtures with various mass fraction at the temperature ranges from 288.15 to 308.15 K: (a), dichloromethane + methanol; (b), dichloromethane + ethanol; (c), dichloromethane + n-propanol; (d), dichloromethane + n-butanol

Mole fraction solubility of itraconazole in chloroform + primary alcohol mixtures with various mass fraction at the temperature ranges from 288.15 to 308.15 K: (a), chloroform + methanol; (b), chloroform + ethanol; (c), chloroform + n-propanol; (d), chloroform + n-butanol.